Apolipoprotein E (ApoE) - e2, e3, and e4 Variants

Apolipoprotein E (ApoE) is a plasma protein found in chylomicrons and very-low-density lipoproteins (VLDL). It plays a critical role in lipid and cholesterol metabolism in the brain and throughout the body.

Fatty acids and cholesterol are key components of cell membranes, precursors of steroid hormones, vitamin D, and bile acids, and are essential for the functioning of the central nervous system.
 

Function of ApoE:

• Lipid Transport: ApoE facilitates cholesterol and lipid transport from synthesis or absorption sites to tissues.
• Metabolism Regulation: It regulates the metabolism of lipoproteins and helps remove excess chylomicrons and low-density lipoproteins (LDL) from the blood by binding to receptors in liver and peripheral cells.
• Brain Cholesterol Management: In the brain, ApoE is synthesized by astrocytes and microglia, transporting cholesterol to neurons for proper functioning.

  ApoE Gene and Variants:

• Gene Structure: ApoE is encoded by the ApoE gene on chromosome 19 and exhibits polymorphism, resulting in three primary variants: E2, E3, and E4.
• Variants: These arise from two single amino acid substitutions at positions 130 and 176:
  • E2: Contains cysteine at both positions.
  • E3: Contains cysteine at position 130 and arginine at position 176.
  • E4: Contains arginine at both positions.

    Genotypes:

    The gene is inherited from both parents, resulting in six possible combinations:

  • E2/E2
  • E2/E3
  • E3/E3 (most common; ~60% of the population; considered normal)
  • E4/E2
  • E4/E3
  • E4/E4

    Health Implications of ApoE Variants:

  • E2 Variant:

    • Increases the risk of Type III Hyperlipoproteinemia (HLP) when two copies are present.
    • Leads to elevated cholesterol and triglycerides.

  • E4 Variant:

• Associated with an increased risk of cardiovascular diseases (e.g., atherosclerosis, myocardial infarction, stroke).
• Strongly linked to Alzheimer’s disease:
• One copy of E4 increases the risk.
• Two copies significantly heighten the risk.
• Linked to poor recovery from traumatic brain injury (TBI) or stroke.

E3 Variant:

• The most common and neutral variant, not associated with heightened disease risk.